Due to the blood-aqueous and blood-retina barriers, it is difficult to get medicines administrated via the systemic route into the eye itself. Doses large enough to overcome these barriers often result in unacceptable systemic side effects. Virtually all acute and chronic disease of the eye are therefore treated with medication in the form of topical eye drop formulations that are applied at least once per day.
In addition to being difficult for patients to insert accurately, the use of eye drops suffers from two major technical disadvantages, their rapid elimination from the eye and their poor bioavailability to the target tissues. As a result of tear film dilution and elimination and the permeability barriers of the cornea, typically less than five percent of the applied dose of drug reaches the intraocular tissues. Topical ophthalmic pharmaceutical solutions are therefore formulated in high concentrations and require frequent dosing. Non-compliance with treatment, due to required frequency of dosing, lack of detectable symptom relief in immediate association with treatment application, undesirable systemic side effects due to the need for high concentrations of drug and other reasons, is a major clinical disadvantage.
The idea of placing a solid device into or near the eye to deliver a drug or a lubricant over time is not new. Most recent scientific interest in this field stems from advances in surgical techniques, pharmacology and pharmacokinetics, as well as the availability of improved polymer systems that can be tailored to the specific needs of ocular drug delivery. For clarity, the distinction should be made between a device that is “inserted into the eye”, meaning placed under the eyelids, external to the eyeball itself, and traditionally referred to as an “ocular insert”, vs. a device that is inserted into the eye surgically, meaning an intraocular insert placed inside the eyeball, or partly inside the eyeball itself. In fact, some devices are implanted in the layers of connective tissue forming the globe of the eyeball, and may even extend through these layers into the eyeball. And some that could be inserted topically under the eyelids could also be surgically implanted under the outermost layer, the conjunctiva, anteriorly, or Tenon's capsule, posteriorly, and would correctly be referred to as subconjunctival or sub-Tenon's inserts. This would be done via a minimally invasive procedure that does not open into the eyeball itself, but rather into the space currently utilized by ophthalmologists for subconjunctival or sub-Tenon's injections.
Saettone concisely stated the case for ophthalmic inserts as set forth in the following points: (Saettone, in Chapter 4, Biopharmaceutics of Ocular Drug Delivery, Edman P, ed., CRC Press, London, 1993, 61-79.).                1. Increased ocular permanence with respect to standard vehicles, hence a prolonged treatment activity and a higher drug bioavailability        2. Accurate dosing (all of the drug is theoretically retained at the absorption site)        3. Possible reduction of systemic absorption, which occurs freely with standard eye drops via the nasal mucosa.        4. Better patient compliance resulting from a reduced frequency of medication and a lower incidence of visual and systemic side effects        5. Possibility of targeting internal ocular tissues through non-corneal (conjunctival-scleral) penetration mutes        6. Increased shelf life with respect to eye drops, due to the absence of water        7. Possibility of providing a constant rate of drug release        
Prior art has concerned itself with fitting a device under the eyelid into the conjunctival potential space. The goal to date has been to retain the device in this potential space, or potential pocket, formed by the palpebral portion of the conjunctiva (lining the inside of the eyelid) and the bulbar portion of the conjunctiva (lining the outside of the front half of the eyeball). The deeper parts of this potential pocket are the loose folds of the conjunctiva referred to as the conjunctival formix or conjunctival cul-de-sac. This potential pocket of continuos tissue is limited by the eyelid margins, near the eyelashes, and the corneal limbus, the circle forming the border of the cornea with the white of the eye. It is referred to as potential space because it not particularly “designed” to hold anything normally, but rather the excess tissue allows movement of the eyeball in the orbit and retains foreign bodies and the tear film from going behind the eyeball into the head or brain. Being a soft, mucus membrane tissue, the conjunctiva easily swells in response to allergens or infection. The space it occupies is therefore potentially expandable by its outward pressure on the eyelids.
Devices meant to be inserted into this potential space have many shapes and sizes, and are often designed from the engineering standpoint of ease of manufacture (Land D, Benjamin W., Sizes and Shapes of Conjunctival Inserts. ICLC. 21: November/December 212-217, 1994). Resulting shapes are simple, such as oblong rectangular, cylindrical, etc. Their sizes and shapes are predicated on the art of tablet manufacture and the desire to be inconspicuous in situ. That is, comfort and retention in the conjunctival sac is attained by slipping something into the pocket formed by the conjunctiva lining the eyeball and the inside of the eyelid, and presuming it would be tolerated by the subject by virtue of its small size. This lack of design specific to the limiting contours of the intended space leads to discomfort and ejection of devices of any significant volume. This limitation of overall dimensions in turn significantly restricts the amount of drug they are able to contain and consequently deliver. An example of a commercially produced ocular insert for drug delivery is found in the subject of U.S. Pat. No. 3,618,604, the Ocusert®, assigned to Alza Corporation. This product was designed from an engineering standpoint of making a drug-releasing “sandwich”. Adequate retention and comfort were assumed by virtue of its small size. Several subsequent patents assigned to Alza Corporation (U.S. Pat. Nos. 3,416,530, 3,828,777) also describe devices that are designed to improve drug delivery kinetics based primarily on material characteristics. These patents address design only in that the devices are “adapted for insertion in the cul-de-sac of the conjunctiva between the sclera of the eyeball and the lower lid, to be held in place against the eyeball by the pressure of the lid”. Although they are in fact quite small in comparison to the present invention, significant problems in retention and irritation with the use of the Ocusert® devices are reported in the literature (Sihvola P, et al. Practical Problems in the Use of Ocusert-Pilocarpine Delivery System. Acta Ophthalmol. (Copenh.), 58 (6) 933-937, 1980). In fact, the products have recently been discontinued, having never been widely accepted or used clinically.
Another example of prior art that utilizes the potential space of the conjunctival cul-de-sac is that of Benjamin in U.S. Pat. No. 6,217,896. Benjamin, noting the failure to do so in the prior art, proposes to maximize the use of the actual volume and shape that could be contained in the cul-de-sac, addressing improved conformity, larger drug capacity and increased stability within the sacs. His design is a result of maximally filling the potential space of the conjunctival cul-de-sac with a molding material, and describing the resulting shape obtained. Although his design description includes a back curvature conforming somewhat to the bulbar surface, this results from his approach of maximizing the volume and shape that could be contained in the human conjunctival sac. The features that he describes as unique to his design are those of the dimensions and volume of the expanded sac itself: “a crescent shape horizontally; a thick inferior horizontal ridge and a wedge-like shape sagittally”. The lack of well-defined mathematical dimensions or expressions for the design, or even a consistent recommended relationship between the back curvature and the bulbar surface, confirm his approach of molding the potential space by expanding it with molding material. As with other prior art, his invention is not designed to fit the eyeball itself and fits the potential space as an empirically derived molded design. Pulling the eyelid away from the globe would result in the insert sliding out of correct position or orientation and/or falling out of the eye.
Another example of prior art that includes a back curvature conforming to the bulbar surface also pursues the engineering approach of fitting a device into the potential space under the eyelid rather than fitting the eyeball itself. In U.S. Pat. No. 3,416,530, Ness describes an “Eyeball Medication Dispensing Tablet”. The hollow chamber of this patent is quite small, in order to comfortably fit in the cul-de-sac.
Much of the prior art depends on material flexibility to achieve retention, without specifying the material of the device or any values or ranges for the flexibility claimed. In WO 01/32140 A1 to Darougar, flexibility is claimed in claim 1 as being sufficient to allow bending along the curvature of the eye within the upper or lower formix upon being positioned, such that the device does not extend onto any visible portion of the eyeball. The flexibility of Darougar et al is intended to allow entrapment of a long, thin device in the conjunctival folds of the formix, and specifically excludes contact with the eyeball. The scope of the design of our invention allows incorporation of materials of any flexibility.
It is important to note that, other than Benjamin in U.S. Pat. No. 6,217,896, the history of the art of ocular inserts for drug delivery has been one of creating small devices, designed to be inconspicuous to the wearer while being trapped in the folds of the conjunctiva or between the eyelid and the globe. This has been addressed primarily by virtue of small size, and secondarily by virtue of shape. Special design features for stability consist of anchors to assist in entrapment, such as the protrusions mentioned in some prior art, such as WO 01/32140 A1 to Darougar, where the protrusions are quite small and are proposed as anchors to assist in entrapment of a long, thin rod-shaped device and render it undetectable in the conjunctival folds of the formix. Examples of prior art of considerably small volumes include the Ocusert® described above and the subject of U.S. Pat. No. 3,828,777, which measures at most 5.7×13.4 mm on its axes and 0.5 mm in thickness, yielding 38.5 μl volume. EPA-0262893 to Darougar discloses a rod-like ocular insert device having a volume of 17 μl. These restrictions on volume significantly limit the amount and subsequent duration of practical drug delivery to the eye.
When reviewing the prior art it is evident that the need exists for an ocular device that is both stable and comfortable in the eye, yet has the volume and mass to deliver therapeutic agents at a controlled rate over an extended period of time.